Components of anesthesia – Amnesia, analgesia, relaxation.

Types of anesthesia

• General – Describes a loss of sensory perception over the entire body. Requires the use of many different agents (narcotics, inhalation agents, muscle relaxants).

• Regional – Describes a loss of sensory perception over a specific part of the body (spinal, epidural, axillary, ankle block). Local anesthetics are used.

• Local – Describes a loss of sensory perception over a very small area of the body. Local anesthetics are used.

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Phases of anesthesia – Induction (putting someone to sleep), maintenance, emergence.

Rules for differentiating amides and esters – Amides have an “i” before “-caine.”

MOA of local anesthetics – Block nerve conduction reversibly by blocking Na+ channels, which prevents depolarization and propagation of nerve impulses.

Conduction blocking factors

• Lipid solubility – Determines anesthetic potency.

• Degree of protein binding – Determines duration of action.

• pKa – All anesthetics are weakly basic with pKa of about 8. Anesthetics can be manipulated by adding small amounts of bicarbonate at the time of administration. This drives the anesthetic toward the non-ionized form. The more non-ionized the anesthetic, the greater the diffusion across the membrane, which speeds the rate of onset.

Anesthetic use with epinephrine – Allows greater duration of anesthetic effect. Can lead to hypoxic necrosis in areas with reduced blood flow.

Complications

• Traumatic injury to nerves

• Infection

• Bleeding

• Tissue neurotoxic reactions

• Hypoxic brain damage

• Allergic reactions – To some amino esters due to release of PABA.

• Systemic toxic reactions

New safer anesthetics – Compared with bupivicaine. Ropivicaine is structurally similar but doesn’t have the toxic effects (removed R enantiomer). Levo-bupivicaine has the bad stuff separated out.

Neuromuscular blockade – Muscle relaxants are necessary to facilitate intubation, provide muscle relaxation during surgery, and facilitate artificial ventilation. They act on two different cholinergic receptors: muscarinic and nicotinc.

Classes of muscle relaxants – Non-depolarizers and depolarizers (succinycholine)

• Non depolarizers – Competitive inhibitors of acetylcholine at the receptor. Virtually all have “cur” in their names (cis-atricuronium & rapidcuronium). To reverse the blocking effects of these drugs, one must administer an acetylcholinesterase inhibitor such as neostigmine or edrophonium. Additionally, with the increase in acetylcholine that results from use of inhibitor, you will get increased muscarinic effects such as bradycardia and the potential for asystole, so one must give an anti-muscarinic such as atropine or glycopyrolate (preferred because it does not cross BBB).

• Depolarizers – Bind to the receptor and cause fasciculations and then sit there for 5-10 minutes. Succinylcholine (metabolized by plasma pseudocholinesterase) is the only on used clinically but has numerous side effects:

  • Fasciculations – Prevent by giving a small dose of nondepolarizer (defasciculating dose).

  • Malignant hyperthermia – Treat with dantrolene.

  
  

Twitch monitor – Usually goes on ulnar nerve. The twitch monitor will NOT tell you how fully recovered the patient is. Train of Four – if no twitches, 95% or more of receptors are blocked; 1 of 4, 90% blockade; 2 of 4, 80%, 3 of 4, 75%; 4 of 4, 65%. The best it can tell you is that there are 2/3 of receptors still blocked. That is why the twitch monitor is used intraoperatively but not for signs of recovery.

Signs of recovery – Lift head up and hand grip (33% receptor block). Clinical signs are important.

Muscle relaxants – You don’t have to use them to intubate, but it makes things easier. Used to facilitate intubation and induction. Used to promote ideal conditions. Effects are monitored with an electric nerve stimulator and by observing clinical signs.

Stages and signs of general anesthesia – Stage I (analgesia); stage II (delirium); stage III (surgical anesthesia); stage 4 (medullary paralysis).

Bispectral index monitor – Measures the relative degree of anesthesia to prevent light anesthesia. Processed EEG (100 is wide awake). Signs of light anesthesia include body movement, increased heart rate and BP.

Inhalation anesthetics – Characteristics are controllability and non-specificity.

Factors that determine uptake of a volatile anesthetic – CO, solubility, uptake = [lambdaQ(Pa-Pv)]/barometric pressure. Lambda is the blood:gas coefficient and is directly related to solubility

Potency – Measured by the minimum alveolar concentration (MAC). MAC of 1 is the concentration at which there is a 50% response to painful stimuli. MAC of 1.3 is the dose at which 100% of patients will not move. Supplement general anesthetic with NO unless contraindicated because NO has less effect on cardiac and pulmonary systems than inhalation agents.

Factors affecting MAC – Older age and pregnancy DECREASE MAC; alcohol abuse INCREASES MAC.

Side effects of inhalation agents – Increases respiratory rate, decreases tidal volume in a dose-dependent matter, overall a slight respiratory depression with a slight decrease in carbon dioxide.

• Halothane – Nonflammable, as are all agents developed in the last 40 yrs; halothane hepatitis associated with repeated anesthesia, hypoxia, and female patients and due to reductive metabolism (which liberates fluoride); all can causes malignant hyperthermia (dantrolene is DOC for treatment of malignant hyperthermia); not used much anymore.

• Isoflurane – Pungent, potent, and nonflammable; much better recovery profile than halothane (15 minutes); used for outpatient procedures; recently replaced by desflurane and sevoflurane.

• Desflurane – Shortest recovery period so very useful in outpatient setting.

• Sevoflurane – Now used in place of halothane in pediatric inductions (better profile).

• Nitrous oxide – Only gas used to aid in general anesthesia.

IV anesthesia – Desirable characteristics include rapid onset, short duration, high clearance, minimal side effects, cost effectiveness, residual analgesia, and rapid recovery

Barbituates

• Thiopental sodium – Potent, ultra short-acting, works in 5-10 sec; side effects include depression of circulation and ventilation; highly lipid soluble.

• Methohexital

Non-barbituates

• Etomidate – Imidazole; minimal cardiorespiratory depression; excellent for elderly patients and asthmatics (no histamine release).

• Propofol – White milky substance; causes quicker emergence than barbs; heavily used in outpatient setting.

Note: Both barbs and non-barbs have no analgesic properties and no muscle-relaxing properties in normal doses.

Ketamine – PCP derivative; rich analgesic effects; increases heart rate and blood pressure (good for trauma patient); can produce nightmares.

Benzodiazepines – Far safer than barbs but strong potential for addiction; used as pre-anesthetic medications to reduce anxiety and produce some amnesia; no significant cardiorespiratory depression; NO analgesic properties either; work at GABA receptors in the amygdala, hippocampus, and prefrontal cortex; causes hyperpolarization thru opening of Cl- channels.

• Diazepam (Valium) – Lasts 20-40 hrs; half-life is 1 hr per age of patient once over 60 yrs old; very addictive; very few depressive effects.

• Lorazepam (Adavan) – Half-life of 10-20 hrs;

• Midazolam (Verced) – Good preoperative drug.

• Flumazenil – BENZODIAZEPINE RECEPTOR ANTAGONIST used to reverse effects of benzos; fast-acting and very selective.

Narcotics – Often given as a supplement to volatile anesthetics and contribute to the MAC. All narcotics cause a dose-dependent respiratory depression.

• Fentanyl – 100x more potent than morphine; minimal cardiac depression; must be given IV; works for 90 min; no histamine release.

• Sulfentanyl – 1000x more potent than morphine; no histamine release.

• Meperidine (Demerol) – Atropine-like structure; 1/10 as potent as morphine; rarely used due to interaction with MAO inhibitors (LETHAL).

Novel agents

• Remifentanil

• Toradol – NSAID that is nearly as potent as morphine; no respiratory depression; affects bleeding profile.

• Ondansetron – Potent anti-emteic used for chemo patients and in the OR with nausea-associated narcotics and general anesthetics; 5-HT subtype 3 antagonist.

Volume of distribution (V_d):

V_d = amount of drug/concentration of drug in plasma

V_d = dose

C_p

AUC: the area under the plasma or blood-concentration:time curve.

Bioavailability: F = AUC (oral)

AUC (IV)

MEC: usually a minimum effective concentration (i.e., MTC minimum therapeutic concentration) of drug in the blood or plasma is needed for a therapeutic effect.

Clearance:

A. The rate of elimination of a drug by all routes relative to the concentration of the drug in a biological fluid (usually blood or plasma).

CL = rate of elimination / concentration_plasma

B. CL = KV_d

K = elimination rate constant

Elimination kinetics:

A. 1st order kinetics:

1. Half-life:

t2 = 0.693V_d / CL

CL = KV_d so t2 = 0.693

K

B. 0 order kinetics:

A constant amount of the drug is eliminated in a given period of time.

A half-life cannot be described.

From: Katzung

Concentration kinetics:

log C = log C₀ -k (t)

2.3

-k = log C₁ - log C

2.3 t₁ - t₂

Plateau levels of a drug (given such that administration rate equals rate of elimination) are reach after four and one-half-lives (i.e., 4.5 x t2)

B. Loading dose

LD = V_d x C_p

Renal disease: D_r = (D) CL_sr

CL_s

T_r = (T) CL_s

CL_sr

creatinine clearance = 160 - age (years) x weight (kg)

(L/h) 22 x serum creatinine (mg/dL) 70

The predicted clearance in women is 90% of the value calculated above.

Squamous cell carcinoma: (60-80% of carcinomas of the cervix) are one of the most common tumour in women (peak incidence 40-45 years old)

Morphology: these cancers arise from precursor lesions; classified according to the degree of epithelial maturation and the distribution of cytologic atypia…

• CIN I: (including condyloma), in which the atypia is predominately in the superficial cell layers (koilocytosis), with preservation of epithelial maturation.

• CIN II: in which the atypia is conspicuous in both the superficial and the basal cell layers, but with decreasing maturation.

• CIN III: in which the atypia is in all cell layers but with minimal or no maturation (carcinoma in situ)

Macroscopically: invasive cervical carcinoma manifests itself in three gross morphologic patterns:

• Exophytic or fungating

• Ulcerating

• Infiltrative

Microscopically: SCC can be classified according to the degree of differentiation:

• Keratinizing (nests), large, well differentiated (25%)

• Non-keratinizing, large cell moderately differentiated (65%)

• Undifferentiated squamous cells (remaining 10%)

Natural History:

Risk of progression to malignancy is proportional to the grade of CIN, but the rates of progression are not uniform. Carcinoma in situ is clearly a precursor of invasive carcinoma, the latter developing in up to 70% of women followed without treatment after a diagnosis of carcinoma in situ.

Stages of cervical cancer are as follows:

Carcinoma in situ (100% cure)…

1. Carcinoma confined to the cervix (80-90% survival)

   • IA: preclinical carcinoma diagnosed only by microscopy

   • IB: Histologically invasive carcinoma greater than 5mm in depth

2. Carcinoma extends beyond the cervix but not into the pelvic wall; into the vagina but not the lower third (75% survival)

3. Carcinoma extends to the pelvic wall or lower third of the vagina (35% survival)

4. Carcinoma has extended beyond the pelvis or metastasized (10-15% survival)

Clinical features and complications:

Clinically tumours may present with:

• Abnormal Pap smear

• Vaginal bleeding or discharge

• Pain or bleeding on coitus

• Hematuria

• Weight loss

Cervical tumours especially squamous carcinomas tend to grow by local spread often involving the urinary system. Death may be due to ureteric obstruction leading to hydronephrosis, pyelonephritis and renal failure.